Numerous advances have been made in both the classification and prognosis of acute myelogenous leukemia (AML) based on recent molecular observations. While the inherent heterogenous nature of AML was initially described using the French-American-British classification, the discoveries of unique chromosomal translocations, gene amplification and mutations and their effects on prognosis and response to therapy have resulted in new and more clinically relevant classification systems. Despite these advances, the mainstay for AML treatment has remained chemotherapy. Targeted therapy has played a role in the treatment of selective AML subtypes. Treatment of acute promyelocytic leukemia (APL) with pharmacologic concentrations of trans-retinoic acid (tRA) results in 90% of the patients achieving a complete remission. This dramatic response of APL cells to high concentrations of tRA is due to the presence of a unique t(15:17) reciprocal translocation resulting in the generation of a promyelocytic leukemia (PML)-retinoic acid nuclear receptor (RAR)α fusion product which, even in the presence of physiologic concentrations of tRA, displays increased binding to co-repressors and induces maturation arrest at the promyelocyte stage. Exposure of these cells to micromolar concentrations of tRA results in the disassociation of PML-RAR from the co-repressors, enhancing its binding by co-activators with the subsequent initiation of gene transcription. Unfortunately, tRA efficacy is restricted to APL with no activity demonstrated in the other AML subtypes. Moreover, with tRA inducing its own catabolism, maintenance therapy may be ineffective with time. New targeted agents including fms-related tyrosine kinase receptor (FLT-3) and farnesyltransferase inhibitors are being evaluated as potential therapeutic modalities for the treatment of AML.
Adamantyl-substituted retinoid-related (ARR) molecules are a unique class of compounds which have been found to induce apoptosis in a large number of tumor types, many of which display resistance to classical retinoids such as tRA. The mechanism(s) utilized by the ARRs in the induction of cell death is not clear. 6-[3-(1-Adamantyl)-4-hydroxyphenyl]-2-naphthalenecarboxylic acid (CD437/AHPN) while initially determined to be a selective activator of the retinoic acid receptors (RARs) β and γ, has been found in numerous studies to inhibit cell growth and induce apoptosis in a variety of malignant cell types utilizing a RAR and retinoid X receptor (RXR)-independent mechanism. In addition, 4-[3-(1-adamantyl)-4-hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC) which binds to the RARs but does not activate the RARs or RXRs is a potent inducer of apoptosis of AML cells in vitro. Recent reports suggest that the novel nuclear receptor, the small nuclear heterodimer partner (SHP, NR0B2), is involved in the induction of apoptosis by the ARRs.
Despite the reports cited above there is currently a need for additional chemical agents that are useful for inducing apoptosis and/or for treating cancer and in particular for treating leukemias. There is also a need for apoptosis inducers and anticancer agents that have enhanced activity or that have improved pharmacologic properties such as increased solubility or better bioavailability. There is also a need for apoptosis inducers and/or anticancer agents that are less toxic or that have an enhanced therapeutic window.